Obesity has reached epidemic levels worldwide. It is associated with major chronic diseases, including cancer and cardiovascular disease. The etiology of obesity-associated cancer is poorly understood. New population-based research mouse models are required to better understand prevention and to increase the translational potential of mouse models to humans. The Collaborative Cross (CC) recombinant inbred lines of mice are a population-based model created from an 8-way multiparental advanced generation intercross with a 12% minor allele frequency (MAF) and more than 45 million SNP and CNV, including a significant number of private (unique) alleles. The Diversity Outbred (DO) mice were created from early CC incipient lines (generations G2:F2-5) by random selection and 175 randomly selected breeding pairs. The genetic diversity of the DO and CC RIL mice is ideal for forward and reverse genetics approaches, respectively, to identify potential causally related risk variants and identify etiology based upon causal relationships. Here, we present data from two cohorts (from different breeding generations) of 50 female and 50 male DO mice each (total 100 each sex). After 12-wks high-fat (60% kcal fat) diet we observed significant differences in weight gain during diet-induced obesity DIO. After switching diets for 8-wks of 30% caloric restriction of a low-fat (10% kcal fat) diet, we observed significant interindividual differences in weight loss. Body weight, lean and fat mass differences), increases in 4-hr fasted blood glucose and insulin levels, insulin resistance (HOMA-IR and increased blood branched chain amino acids levels (BCAA) were observed. Four interacting quantitative trait loci/gene (Chst10, Bmiq5, Ath8, and Tcq14) related to metabolism, body mass index, cardiovascular disease, and total cholesterol levels, respectively, have been identified. Regression analysis suggests significant interactions between fasted blood glucose and fat mass, HOMA-IR and fat mass, and BCAA and fat mass in DIO and CR outcomes. Results to date show significant amounts of interindividual variability of each of the quantified phenotypes in response to both diet interventions were demonstrated in female and male DO mice. These data suggest potential avenues of research on obesity and cancer relationships and pathways for intervention.

Citation Format: Melissa VerHague, Jody Albright, Salvador Favela, Kerri Barron, Michael F. Coleman, Katie Meyer, John E. French, Stephen D. Hursting. Diet-induced obesity and caloric restriction weight loss in Diversity Outbred (DO) mice: An experimental preclinical translational model for the investigation of pathways for prevention of obesity and cancer [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A45.